Both u-PA inhibition and vitronectin binding by plasminogen activator inhibitor 1 regulate HT1080 fibrosarcoma cell metastasis

Michael Praus, Désiré Collen, Robert D. Gerard

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Overexpression of plasminogen activator inhibitor 1 (PAI-1) reduces tumor cell migration in vitro and metastasis in mice in vivo by mechanisms involving either inhibition of urokinase plasminogen activator (u-PA) activity or competition for an integrin binding site on vitronectin. To analyze the effects of PAI-1 on tumor cell migration in vitro and metastasis in vivo, recombinant adenoviral vectors expressing wild-type or mutant PAI-1 proteins were constructed. The mutant PAI-1 proteins were defective in either vitronectin binding (PAI-1VN-), plasminogen activator inhibition (PAI-1INH-) or both (PAI-1VN-,INH-). In vitro, migration of HT1080 human fibrosarcoma cells through a reconstituted extracellular matrix (ECM) was reduced 73% by overexpression of wild-type PAI-1 and 65% by PAI-1VN- compared with control virus-infected cells. Migration of cells infected by virus expressing either PAI-1INH- or PAI-1VN-,INH- was unaffected, indicating a requirement for plasminogen activator inhibitory activity. In vivo, however, only overexpression of wild-type PAI-1 reduced the burden of metastasis by 68% compared with the control group. This indicates that both u-PA inhibition and PAI-1 ECM interactions contribute to the mechanism of PAI-1-mediated regulation of cell migration.

Original languageEnglish (US)
Pages (from-to)584-591
Number of pages8
JournalInternational Journal of Cancer
Volume102
Issue number6
DOIs
StatePublished - Dec 20 2002

Keywords

  • Adenovirus
  • Cell movement
  • Gene transfer
  • Neoplasm metastasis
  • Plasminogen activator inhibitor 1
  • Vitronectin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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